R.K. Bryneshttp://repub.eur.nl/ppl/6636/
List of Publicationsenhttp://repub.eur.nl/eur_signature.pnghttp://repub.eur.nl/
RePub, Erasmus University RepositoryMutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropeniahttp://repub.eur.nl/pub/60338/
Thu, 24 Aug 1995 00:00:01 GMT<div>F. Dong</div><div>R.K. Brynes</div><div>N. Tidow</div><div>K. Welte</div><div>B. Löwenberg</div><div>I.P. Touw</div>
In severe congenital neutropenia the maturation of myeloid progenitor cells is arrested. The myelodysplastic syndrome and acute myeloid leukemia develop in some patients with severe congenital neutropenia. Abnormalities in the signal-transduction pathways for granulocyte colony-stimulating factor (G-CSF) may play a part in the progression to acute myeloid leukemia.Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropeniahttp://repub.eur.nl/pub/8534/
Sun, 01 Jan 1995 00:00:01 GMT<div>F. Dong</div><div>R.K. Brynes</div><div>N. Tidow</div><div>K. Welte</div><div>B. Löwenberg</div><div>I.P. Touw</div>
BACKGROUND. In severe congenital neutropenia the maturation of myeloid
progenitor cells is arrested. The myelodysplastic syndrome and acute
myeloid leukemia develop in some patients with severe congenital
neutropenia. Abnormalities in the signal-transduction pathways for
granulocyte colony-stimulating factor (G-CSF) may play a part in the
progression to acute myeloid leukemia. METHODS. We isolated genomic DNA
and RNA from hematopoietic cells obtained from two patients with acute
myeloid leukemia and histories of severe congenital neutropenia. The
nucleotide sequences encoding the cytoplasmic domain of the G-CSF receptor
were amplified by means of the polymerase chain reaction and sequenced.
Murine myeloid 32D.C10 cells were transfected with complementary DNA
encoding the wild-type or mutant G-CSF receptors and tested for their
responses to G-CSF. RESULTS. Point mutations in the gene for the G-CSF
receptor were identified in both patients. The mutations, a substitution
of thymine for cytosine at the codon for glutamine at position 718
(Gln718) in one patient and at the codon for glutamine at position
731(Gln731) in the other, caused a truncation of the C-terminal
cytoplasmic region of the receptor. Both mutant and wild-type genes for
the G-CSF receptor were present in leukemic cells from the two patients.
In one patient, the mutation was also found in the neutropenic stage,
before the progression to acute myeloid leukemia. The 32D.C10 cells
expressing mutant receptors had abnormally high proliferative responses
but failed to mature when cultured in G-CSF. The mutant G-CSF receptors
also interfered with terminal maturation mediated by the wild-type G-CSF
receptor in the 32D.C10 cells that coexpressed the wild-type and mutant
receptors. CONCLUSIONS. Mutations in the gene for the G-CSF receptor that
interrupt signals required for the maturation of myeloid cells are
involved in the pathogenesis of severe congenital neutropenia and
associated with the progression to acute myeloid leukemia.